DISCOVERY OF INDOLYL PIPERAZINYLPYRIMIDINES WITH DUAL-TARGET PROFILES ADENOSINE A2¿ AND DOPAMINE D2 RECEPTORS FOR PD TREATMENT

Abstract

PARKINSON¿S DISEASE (PD) IS A PREVALENT NEURODEGENERATIVE MOVEMENT DISORDER CHARACTERISED PATHOLOGICALLY BY THE LOSS OF DOPAMINERGIC NEURONS IN THE SUBSTANTIA NIGRA. THE CURRENT PHARMACOTHERAPIES OF PD ARE FACING LIMITATIONS ON SIDE EFFECTS, SUCH AS MOTOR FLUCTUATIONS, DRUG-INDUCED DYSKINESIA, AND PSYCHOSIS. THIS THESIS SEEKS TO ADDRESS THESE LIMITATIONS BY DISCOVERING NEW CHEMICAL ENTITIES (NCES) TARGETING ADENOSINE HA2A AND DOPAMINE HD2 RECEPTORS AS NOVEL THERAPEUTICS OF PD. THREE COMPUTATIONAL METHODS, NAMELY SUPPORT VECTOR MACHINE (SVM) MODELS, TANIMOTO SIMILARITY, AND HIERARCHICAL CLUSTERING, WERE UTILISED FOR THE IDENTIFICATION OF COMPOUNDS CONTAINING THE [INDOLE + PIPERAZINE + PYRIMIDINE] (IPP). SUBSEQUENT SYNTHESIS AND TESTING OF IPP-CONTAINING COMPOUNDS LED TO THE DISCOVERY OF DUAL-ACTING COMPOUNDS 69 AND 70.